The major thrust of these proposed investigations is the insulin receptor. Particular emphasis will be placed on study of down regulation. The role of hyperinsulinism and down regulation in the alleged reduced insulin receptor population of chemical diabetes will be determined. In addition, a possible secondary role of down regulation in the pathogenesis of the diabetic state will be assessed. These clinical studies will be accompanied by more basic studies into the mechanism of down regulation of insulin receptors. A search for other substances that down regulate insulin receptors as well as a possible second messenger of the effect will be examined. An attempt to establish a radioimmunoassay for the insulin receptor will be made. Solubulized receptors will be looked for in biologic fluids and subcellular fractions. In addition, a number of studies are planned to examine the biological effects of the purified anti-receptor antibody. Such studies include the biologic effects on cultured hepatocytes, the capacity of the antibody to down regulate receptors and to participate in cooperative reactions. The antibody will also be used to determine the importance of insulin receptors on pancreatic alpha and beta cells. Finally, plans to establish a model for examining receptor occupancy-biological activity relationships using the cultured adult hepatocyte in monolayer are presented. With such a model, defects in receptors, post-receptor events and the coupling mechanism can be examined. Perturbations to be examined include chronic hyperinsulinism and other pancreatic hormones, metabolic fuels, diabetes, obesity, fasting, extra pancreatic hormones and drugs.